Type1A (MDC1A) is the most common form of congenital muscular dystrophy, which like many other forms of dystrophy lacks an effective treatment at this time. It is caused by mutation of LAMA2, the gene coding for the laminina2 chain, which is indispensable to the structural integrity of the muscle extra-cellular matrix. A major consequence of disrupted laminin expression is severe muscle loss due to accelerated muscle degeneration and limited or absent regeneration. The Lama2Dy-w is a laminina2 deficient mouse and is used as a model for CMD disease in humans. We demonstrated that the members of the Bcl2 family involved in the regulation of apoptosis play a significant role in the pathogenesis in the mouse model of MDC1A, suggesting that apoptosis is important in the progression of the disease. We showed that inactivation of Bax - a pro-apoptotic protein of the Bcl2 family - increases life span and improves both postnatal growth and myofiber histology in Lama2-/- mice. To develop a pharmacological approach to inhibit apoptosis, we treated laminin deficient mice with doxycycline, a drug with both anti-apoptotic and anti-inflammatory effects. Preliminary studies show that in response to doxycycline treatment, laminin deficient mice have dramatic increase in life span, body size, improved locomotor function, and a decreased inflammatory response. However, although significant, these antiapoptotic interventions do not completely prevent disease progression since the dystrophic pathology is still evident in these laminin deficient mice. The goal of the proposed research is to identify additional approaches that could be used for therapeutic interventions to further ameliorate the pathology. More recently, we have demonstrated that mononucleated cells resident in the skeletal muscle of laminin deficient mice have poor proliferative capacity, a process essential for successful regeneration. Based on these observations, we propose to test the consequences of increasing the proliferation of the myogenic mono-nucleated cells by administering exogenous IGF-1 in vivo alone or in conjunction with doxycycline in the Lama2Dy-w mice. IGF-1 pathways have been shown to improve regeneration by facilitating proliferation, differentiation and survival. Results will establish if exogenous treatment with IGF-1 in combination with doxycycline treatment will have an additional improvement in the pathology of Lama2Dy-w mice. The proposed research provides an opportunity to explore an combinatorial therapeutic approach in treating muscle pathology and may have the potential to show a better improvement than inhibition of apoptosis alone. [unreadable] [unreadable] [unreadable]